Cell News | Issue 02, 2014 - page 10

Cell News 2/2014
10
Nikon Young Scientist Award 2014
Hans Zempel
Background
In Alzheimer Disease (AD), the connection of the two major pa-
thological hallmarks, deposition of the extracellular Amyloid-
beta (A
β
) in the form of plaques, and aggregation of the intra-
cellular protein Tau, is not well understood. Genetic evidence
from AD and Down Syndrome (Trisomy 21), and models thereof,
has suggested that aberrant production of A
β
is upstream of
Tau aggregation, but also points to Tau as a critical effector in
the pathological process (Bloom, 2014; Ittner and Gotz, 2010;
Morris et al., 2011). Yet, the cascade of events leading from in-
creased levels of A
β
to Tau-dependent toxicity remains a matter
of debate, hindering rational developments of therapies for AD
and related dementias.
Results
To elucidate the pathological cascade leading to neurodegene-
ration in AD, we established a system to model the effects of
A
β
on Tau. In mature rodent primary neurons, Tau is present
in several isoforms, is sorted into the axonal compartment and
excluded from the somatodendritic compartment, similar to the
adult human brain. To trigger AD-like pathological changes of
Tau, we exposed primary neurons to a pre-aggregation form of
A
β
(oligomeric A
β
), which is thought to be the toxic trigger in
AD (Haass and Selkoe, 2007; Karran et al., 2011). We investiga-
ted changes of Tau and related cellular pathologies using bio-
chemical methods, fluorescence microscopy including live cell
imaging, and electron microscopy.
After exposure to oligomeric A
β
, Tau becomes mislocalized
(missorted) into the somatodendritic compartment. This mis-
sorting of Tau correlates with a loss of synapses specifically in
dendrites containing missorted Tau. This loss of synapses could
link the mislocalization of Tau to the cognitive decline observed
in AD patients. One of the key features discovered here is that
in neurons showing missorted dendritic Tau, there is a dramatic
loss of microtubules (Zempel and Mandelkow, 2012). As tracks of
intracellular traffic, microtubules are of great importance, par-
ticularly for neurons whose extended processes require a high-
ly efficient transport system based on microtubule-dependent
motor proteins. Treatment of neurons with A
β
oligomers leads
Research news
Figure 1.
oligomers
induce missorting of Tau into
dendrites. Missorting of Tau
correlates with loss of spines.
Example of two nearby dendri-
tes after treatment with A
β
oli-
gomers of primary hippocampal
neurons aged for 23 days
in
vitro
. Tau is stained with a
total Tau antibody (K9JA, green
color). Spines are dendritic
protrusions that contain
high amounts of filamentous
actin (f-actin; stained with
phalloidin, red color) and are
indicative of healthy synapses.
The lower dendrite shows the
presence of missorted Tau and
loss of spines (box with solid
outline, arrows), while the
upper dendrite (dotted box,
arrowheads) is free of Tau and
contains numerous spines.
Adapted from (Zempel et al.,
2010).
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